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Butler M, Urosevic S, Desai P, et al. Treatment for Bipolar Disorder in Adults: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Aug. (Comparative Effectiveness Review, No. 208.)
Appendix Table O1Characteristics of eligible studies: combination interventions vs. inactive comparators
| Study, Year Design Location Funder Risk of Bias PMID | Randomized (N) Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting | Inclusions Key Exclusions | Intervention Description | Comparison Description | Followup Duration | Outcomes Reported Withdrawal (%) at endpoint |
|---|---|---|---|---|---|---|
| Gonzalez-Isasi, 20141 Gonzalez-Isasi, 20102 RCT Spain Non-Government Low 20444503 23276524 | N=40 Mean Age 41 (18-63) Female 48% White NR BP NR Outpatient | Euthymic or Subsyndromal; BP I or II (DSM-IV) for at least 2 years, history of severe or unfavorable progression of disease, euthymic or subsyndromal symptoms (BDI>7; YMRS> 6), not receiving any psychotherapy Labs/Other Conditions | Group psychoeducation and CBT consisting of sessions about their disorder, the relationship between thoughts and feelings, anxiety control techniques, cognitive re-structuring, problem-solving and self-esteem, and social skills. -20 weekly sessions, 90 minutes each | Standard pharmacologic treatment (mood stabilizers, antipsychotics, and/or benzodiapines) adjusted by psychiatrist | 5 years | BDI YMRS Hospitalizations Withdrawal 5% |
| Todd, 20143 RCT UK Government and Non-Government Moderate 25129531 | N=122 Age 43 (21-65) Female 72% White 89% BP I 70% BP II 25% Rapid Cycling 5% Outpatient | No current clinical state excluded: Self-reported BP I or II and scoring above a threshold for BP I or II on the MDQ None | Interactive, online recovery informed self-management intervention (Living with Bipolar) based on both psychoeducation and CBT. Ten interactive modules to help subjects learn more about bipolar experiences, increase self-esteem and self-efficacy for managing bipolar, increase ability to self-manage, and develop interpersonal skills. Modules included case studies and mood checking tools. -Access to program for 6 months | Wait list control receiving treatment as usual (general practitioner and/or specialist mental health services). | 6 months | ISS Depression QoL.BD-Brief WHO-QOL-bref SASS Withdrawal 25% |
| Miklowitz 20034 Cohort US Government and Non-Government High 12963672 | N=100 Age 36 (18-55) Female 60% White 89% BP NR Outpatient | No current clinical state excluded; BP I or II (DSM-IV) with a hypo/manic, depressed, or mixed episode within the last 3 months, willingness to be on maintained drug regimen, living with or in regular contact with close relatives Substance Abuse; Neurological Disorders | Individual IPSRT and family (or partner) therapy. Individual IPSRT consisted of identifying interpersonal problems, using Social Rhythm Metric form, managing symptoms and identifying triggers, and relapse prevention. Family therapy involved education about BP, identification of triggers, communication enhancement, and problem-solving. -25 sessions of individual therapy and 25 sessions of family-focused therapy (frequency adapted to patient needs) | Treatment as usual: Crisis management (not described, comparison group from previous clinical trial) | 12 months | Relapse SADS-C Depression SADS-C Mania Time to Recurrence Withdrawal 28% |
Abbreviations: BDI=Beck depression inventory; BP=bipolar disorder; DSM-IV= Diagnostic and statistical manual, 4th edition; ISS=Internal States Scale; MDQ=Mood Disorder Questionnaire; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; QoL.BD-Brief=Quality of Life,Bipolar Disorder; RCT=randomized controlled trial; SADS-C= Schedule for Affective Disorders and Schizophrenia, change version; SASS=Simpson Angus Scale score; WHO-QOL-bref=World Health Organization Quality of Life –short version; YMRS = Young Mania Rating Scale
Appendix Table O2Summary risk of bias assessments: combination interventions vs. inactive comparators
| Study Funder PMID | Overall Risk of Bias Assessment | Rationale |
|---|---|---|
| Gonzalez-Isasi, 20141 Gonzalez-Isasi, 20102 Non-Government 20444503 23276524 | Low | No significant suspected biases. |
| Todd, 20143 Government and Non-Government 25129531 | Moderate | Suspected bias due to process for selection. Participant eligibility was based self-reported diagnosis and online clinical questioonare. |
| Miklowitz 20034 Government and Non-Government 12963672 | High | Suspected bias due to process for selection. Partcipants were not randomized to treatment or comparator arm. Data used for comparison was from a previous study. |
Abbreviations: PMID=PubMed Identification Number
Appendix Table O3Outcomes summary: combination interventions vs. inactive comparators
| Study PMID | Responder/Remitter | Symptom | Function | Other | AE |
|---|---|---|---|---|---|
| Gonzalez-Isasi 20102 20444503 Gonzalez-Isasi 20141 23276524 | NR | Depression* 11 months, BDI Favors combination intervention ES=−0.83 (95% CI −1.47, −0.18) 17 months, BDI Favors combination intervention ES=−1.21 (95% CI −1.89, −0.53) 5 years, BDI Favors combination intervention ES=−2.17 (95% CI −2.95, −1.37) Mania* 11 months, YMRS Favors combination intervention ES=−1.0 (95% CI −1.60, −0.30) 17 months, YMRS Favors combination intervention ES=−1.5 (95% CI −2.2, −0.80) 5 years, YMRS Favors combination intervention ES=−1.10 (95% CI −1.80, −0.40) | NR | Hospitalizations Significant difference between groups at 17-months (p=0.015). No difference at 11-months (p=0.12) or 5-years (p=0.11). | NR |
| Todd 20143 25129531 | NR | Depression* 6 months, ISS Depression Favors combination intervention ES=−0.44 (95% CI −0.83, −0.05) | Quality of Life* 6 months, QoL.BD-Brief Favors combination intervention ES=0.42 (95% CI 0.04, 0.82) Social Function* 6 months, SASS Favors combination intervention ES=0.54 (95% CI 0.14, 0.93) | NR | NR |
| Miklowitz 20034 12963672 | Relapse* 12 months, Any Type NS OR=0.68 (95% CI 0.24, 1.85); p=0.50 Time to Recurrence 12 months Favors combination intervention HR=0.078, p<0.02 42.5 (2.2) weeks IFIT vs. 34.5 (2.5) weeks CM | SADS-C Depression 12 months Favors combination intervention, p < 0.0001. SADS-C Mania 12 months NS, p >0.10 | NR | NR | NR |
Abbreviations: AE=Adverse Events; BDI=Beck depression inventory; CI=Confidence Interval; CM=Clinical Management; ES=Effect Size; HR=Hazard Ratio; IFIT=Integrated Family and Individual Therapy; ISS=Internal States Scale; NR=not reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; QoL.BD-Brief=Quality of Life,Bipolar Disorder; SADS-C=Schedule for Affective Disorders and Schizophrenia-Change version; SASS=Simpson Angus Scale score; YMRS = Young Mania Rating Scale
Appendix Table O4Summary of strength of evidence: combination intervention vs. inactive comparators
| Outcome | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
| Relapse | 12 months | 1 Cohort Study (n=100) | No difference between groups at 12 months. | High | Unclear | Direct | Imprecise | Insufficient |
| Depression | 7-12 months 5 years | 3 RCTs (n=262) | Favors combination intervention across multiple time periods. | Low | Consistent | Direct | Imprecise | Insufficient |
| Mania | 7-12 months 5 years | 2 RCTs (n=140) | Mixed evidence with no clear direction of effect. No pattern across time periods. | Low | Unclear | Direct | Imprecise | Insufficient |
| Global Function | NR | - | - | - | - | - | - | - |
| Other Measures of Function | 6 months | 1 RCT (n=122) | Favors combination intervention at 6 months. | Moderate | Unclear | Direct | Imprecise | Insufficient |
Abbreviations: NR=not reported; RCT=randomized controlled trial
Appendix Table O5Characteristics of eligible studies: combination interventions vs. active comparators
| Study, Year Design Location Funder Risk of Bias PMID | Randomized (N) Age (mean) Sex (% Female) Race (% White) Diagnosis (% BP I, II, NOS) Setting | Inclusions Key Exclusions | Intervention Description | Comparison Description | Followup Duration | Outcomes Reported Withdrawal (%) at endpoint |
|---|---|---|---|---|---|---|
| Fagiolini 20095 RCT US Government Moderate 19500091 | N=463 Age 41 (12-75) Female 61% White 83% BP I 68% BP II 19% BP NOS 11% Schizophrenia 2% Outpatient | No current clinical state excluded; BP I, II, or NOS or schizoaffective bipolar subtype disorder (DSM-IV for adults, KSADS-PL for adolescents). Substance Abuse; Other Mental Health; Pregnant/Nursing; Labs/Other Conditions | Enhanced clinical intervention and specialized care for bipolar disorder. Enhanced clinical intervention consisted of 10 basic elements plus specific modules for young, elderly, and African American patients. Elements consisted of education (on disorder, medications, sleep) and management (review of symptoms, discussion and management of side effects, discussion of early waning signs). Additional non-specific support provided to both patient and families. -Weekly enhanced clinical sessions for 12 weeks, then every other week for 8 weeks, and then monthly for remaining time or until they achieved recurrence | Specialized care for bipolar disorder consisting of a manualized system of clinical management included assessment of quality of life, standardized assessments of mood, comprehensive medical evaluations, frequent visits with treatment team, pharmacological treatment and tracking and monitoring of visits. | 18 months | CGI BP Depression CGI BP Mania GAF QLESQ Withdrawal 30% |
| Zaretsky 20086 RCT Canada Government and Non-Government High 18674402 | N=79 Age 41 (18-60) Female NR White NR BP I 66% BP II 34% Outpatient | Euthymic/Maintenance; BP I or II, not currently in a full episode, taking a standard mood stabilizer regimen with no change in regimen or prescribing physician in month prior to study entry. Substance Abuse; Schizoaffective; Other Mental Health; Neurological Disorders; Labs/Other Conditions | Psychoeducation and CBT. CBT was based on Basco and Rush manual and emphasized collaborative goal setting, cognitive restructuring, problem-solving, and enhancing interpersonal communication. -7 weekly, audiotaped individual sessions of psychoeducation and 13 weekly, audiotaped individual sessions of CBT | Psychoeducation based on the first five chapters of the Basco and Rush CBT manual. -7 weekly, audiotaped individual sessions | 6 months | Relapse HDRS Withdrawal 42% |
Abbreviations: BP=bipolar disorder; CBT=Cognitive Behavioral Therapy; CGI=Clinical Global Impressions Scale; DSM-IV= Diagnostic and statistical manual, 4th edition; GAF=General Assessment of Functioning Scale; HDRS=Hamilton Depression Rating Scale; KSADS-PL=Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version; NOS=not otherwise specified; NR=not reported; PMID=PubMed Identification Number; RCT=randomized controlled trial
Appendix Table O6Summary risk of bias assessments: combination interventions vs. active comparators
| Study Funder PMID | Overall Risk of Bias Assessment | Rationale |
|---|---|---|
| Fagiolini 20095 Government 19500091 | Moderate | Suspected selection bias due to unclear reporting of randomization process. |
| Zaretsky 20086 Government and Non-Government 18674402 | High | Suspected bias selection bias due to unclear reporting of randomization process and suspected bias due to attrition rate of 42%. |
Abbreviations: PMID=PubMed Identification Number
Appendix Table O7Outcomes Summary: combination interventions vs. active comparators
| Study PMID | Responder/Remitter | Symptom | Function | Other | AE |
|---|---|---|---|---|---|
| Fagiolini 20095 19500091 | NR | Depression 18 months, CGI Depression NS Mania 18 months, CGI Mania NS | Global Function 18 months, GAF NS Quality of Life 18 months, QLESQ Favors combination intervention. | NR | NR |
| Zaretsky 20086 18674402 | Relapse* 12 months, Any Type NS OR=1.20 (95% CI 0.23, 6.80); p=0.55 | HDRS 12 months Favors combination intervention, p=0.055 | NR | NR | NR |
Abbreviations: CGI=Clinical global impression scale; CI=Confidence Interval; GAF=General Assessment of Functioning Scale; HDRS=Hamilton Depression Rating Scale; NR=Not Reported; NS=not significant; OR=Odds Ratio; PMID=PubMed Identification Number; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionaire
Appendix Table O8Summary of strength of evidence: combination intervention vs. active comparators
| Outcome | Timing | # Studies/Design (n analyzed) | Finding or Summary Statistic | Study Limitations | Consistency | Directness | Precision | Overall Grade/Conclusion |
|---|---|---|---|---|---|---|---|---|
| Relapse | 12 months | 1 RCT (n=79) | No difference between groups at 12 months. | High | Unclear | Direct | Imprecise | Insufficient |
| Depression | 12 months 18 months | 2 RCTs (n=542) | Mixed evidence with no clear direction of effect. No pattern across time periods. | High | Inconsistent | Direct | Imprecise | Insufficient |
| Mania | 18 months | 1 RCT (n=463) | No difference between groups at 18 months. | High | Unclear | Direct | Imprecise | Insufficient |
| Global Function | 18 months | 1 RCT (n=463) | No difference between groups at 18 months | Moderate | Unclear | Direct | Imprecise | Insufficient |
| Other Measures of Function | 18 months | 1 RCT (n=463) | Favors combination intervention at 18 months. | Moderate | Unclear | Direct | Imprecise | Insufficient |
Abbreviations: RCT=randomized controlled trial
References for Appendix O
- 1.
- Gonzalez Isasi A, Echeburua E, Liminana JM, et al Psychoeducation and cognitive-behavioral therapy for patients with refractory bipolar disorder: A 5-year controlled clinical trial. European Psychiatry. Dec. 2014 March 2014(Pagination)PMID 23276524. [PubMed: 23276524]
- 2.
- Gonzalez-Isasi A, Echeburua E, Mosquera F, et al Long-term efficacy of a psychological intervention program for patients with refractory bipolar disorder: a pilot study. Psychiatry Research. 2010 Apr 30;176(2–3):161–5. PMID 20096466. [PubMed: 20096466]
- 3.
- Todd NJ, Jones SH, Hart A, et al A web-based self-management intervention for Bipolar Disorder ‘living with bipolar’: a feasibility randomised controlled trial. J Affect Disord. 2014 Dec;169:21–9. PMID 25129531. [PubMed: 25129531]
- 4.
- Miklowitz DJ, George EL, Richards JA, et al A randomized study of family-focused psychoeducation and pharmacotherapy in the outpatient management of bipolar disorder. Archives of General Psychiatry. 2003 Sep;60(9):904–12. PMID 12963672. [PubMed: 12963672]
- 5.
- Fagiolini A, Frank E, Axelson DA, et al Enhancing outcomes in patients with bipolar disorder: results from the Bipolar Disorder Center for Pennsylvanians Study. Bipolar Disorders. 2009 Jun;11(4):382–90. PMID 19500091. [PMC free article: PMC3361715] [PubMed: 19500091]
- 6.
- Zaretsky A, Lancee W, Miller C, et al Is cognitive-behavioural therapy more effective than psychoeducation in bipolar disorder? Canadian Journal of Psychiatry - Revue Canadienne de Psychiatrie. 2008 Jul;53(7):441–8. PMID 18674402. [PubMed: 18674402]
- Combination Interventions - Treatment for Bipolar Disorder in Adults: A Systemat...Combination Interventions - Treatment for Bipolar Disorder in Adults: A Systematic Review
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